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Historic aspects in the identification of the I1 receptor and the pharmacology of imidazolines

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Summary

The central nervous system is involved in the control of arterial blood pressure. Stimulation of central α2-adrenoceptors in the nucleus tractus solitarii (NTS) decreases sympathetic outflow, resulting in a fall in arterial blood pressure. One of the first antihypertensive substances with actions on the α2-adrenoceptors of the NTS was α-methylnoradrenaline. Later on the imidazoline clonidine was developed for which numerous effects, mediated by α2-adrenoceptors, in the CNS could be demonstrated. Since the centrally acting α2-adrenoceptor agonists possess severe side effects, the development of more specific and selective centrally acting imidazolines resulted in the derivatives moxonidine and rilmenidine. The effects of the “second-generation imidazolines” could not be fully understood as α2-adrenoceptor agonists. In the meantime, the rostral ventrolateral medulla (RVLM) has been identified as the site of action of the imidazolines and an I1-imidazoline binding site was characterized in this region. For the antihypertensive action of the imidazolines, agonism at the I1-imidazoline subtype seems to be responsible. In addition, an acid- and heat-stable endogenous substance, calledclonidine displacing substance (CDS), was reported to bind at the putative I receptor. In 1992 a receptor protein for I receptors (70 kD) could be separated that is different from that of α2-adrenoceptors. However, up to now we are still lacking the amino-acid sequence of the I receptor and its second messenger system.

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  1. Institute of Pharmacology, Medical University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany

    P. Dominiak

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Dominiak, P. Historic aspects in the identification of the I1 receptor and the pharmacology of imidazolines. Cardiovasc Drug Ther 8 (Suppl 1), 21–26 (1994). https://doi.org/10.1007/BF00877081

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